JP2007506999A - Ophthalmic device including a holographic sensor - Google Patents

Abstract

An ophthalmic apparatus including a holographic sensor is provided.
The present invention is an ophthalmologic apparatus having a holographic element including a medium and a hologram disposed on the medium, and when the physical properties of the medium change, the optical characteristics of the element change, and the medium and the eye The present invention relates to an apparatus characterized in that a change occurs due to an interaction with a specimen in a liquid. An analyte such as glucose can be detected by this apparatus.
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Description

The present invention relates to an ophthalmic apparatus including a holographic sensor.

Ophthalmic devices such as contact lenses including holographic elements are known. In general, a holographic element is used for focusing on incident light. The holographic element may have an operating angle set to produce two or more optical forces. The holographic element allows the user to see a clear and complete image, thus overcoming many of the shortcomings of conventional simultaneous vision and translating lenses. Holographic optical inserts are described, for example, in US Pat.

Numerous studies have been conducted because of the need for a minimally invasive and easy to use glucose sensor. One area of interest is ophthalmic glucose sensors (ie, sensors that detect glucose in the eye). It is known that the eye glucose level and the blood glucose level are related to each other. Therefore, the blood glucose level can be indirectly observed by measurement in ocular fluid such as tears.

Patent Document 5 describes an ophthalmic insert for detecting glucose. The insert includes a polymerized crystal colloidal array (PCCA) polymerized in a hydrogel and a molecular recognition element that is responsive to glucose. The lattice spacing of the array changes due to the volume change of the hydrogel, which changes the diffraction wavelength of the array.

Patent Document 6 discloses a holographic sensor based on a volume hologram. The sensor has an analyte sensitivity matrix that includes a light conversion structure throughout the entire volume. Due to the physical arrangement of the conversion structure, the optical signal emitted from the sensor is very sensitive to volume changes or structural arrangement changes of the analyte sensitivity matrix that occur as a result of the interaction or reaction between the analyte sensitivity matrix and the analyte. For example, trypsin can be detected with a sensor comprising a holographic medium based on gelatin. Trypsin affects the gelatin medium and irreversibly destroys the structure of the consistent holographic support medium. For example, a change in pH or the like can be detected by the holographic sensor.

Although the glucose level in the eye can be detected by the type of sensor described in Patent Document 7, there is still a need for an ophthalmic sensor that can detect a sample such as glucose accurately and in real time.
International Patent WO-A-99 / 34239 International patent WO-A-99 / 34244 International Patent WO-A-02 / 054137 International patent WO-A-99 / 34248 U.S. Patent No. A-2003 / 0027240 International Patent WO-A-95 / 26499 U.S. Patent No. A-2003 / 0027240

SUMMARY OF THE INVENTION The present invention is based on the recognition that it provides a method for detecting ophthalmic specimens accurately and with minimal invasiveness through holographic sensing technology incorporated into contact lenses or other ophthalmic devices. This sensing technique would allow continuous and real-time sensing of glucose or other carbohydrates. Therefore, according to the present invention, the life of a diabetic patient can be improved and the risk of developing low blood glucose or high blood glucose in the diabetic patient can be reduced.

A first aspect of the present invention is an ophthalmologic apparatus, which includes a medium and a holographic element including a hologram disposed on the medium. When the physical property of the medium changes, the optical characteristics of the element change, The apparatus is characterized in that a change occurs due to an interaction with the specimen in the eye fluid. The device may be a contact lens or an ophthalmic implant.

Another aspect of the present invention is a method for detecting an analyte in ophthalmic fluid, comprising detecting any change in the optical properties of the holographic element of the device of the present invention that is present with the liquid in the eye. It is a method to do.

Another aspect of the present invention includes contact between a holographic element and a contact lens, wherein the contact area between the element and the lens is crosslinkable and includes bridging of the contact area. It is a manufacturing method. At least one of the contact areas preferably includes PVA, and more preferably includes Nelfilcon ™.

According to the present invention, ophthalmic specimens such as glucose or lactate can be detected. Preferably, the interaction is reversible, and continuous detection of the analyte, preferably real time, is possible by the occurrence of both interaction and reverse interaction. The interaction is preferably a chemical reaction.

DESCRIPTION OF THE INVENTION The term “glucose” refers herein to cyclic glucose and linear glucose.

The term “ophthalmic device” refers herein to (hard and soft) contact lenses, corneal onlays, implantable ophthalmic devices, and the like.

The term “contact lens” as used herein refers to any hard and soft contact lens used for vision correction, diagnosis, sample collection, drug delivery, wound healing, cosmetic appearance or other ophthalmic applications in or near the eye. . The lens may be a daily disposable lens, a daily wearing lens or a long-wearing lens.

The term “implantable ophthalmic device” as used herein refers to an ophthalmic device used at, on, or around the eye or eye. The devices include intraocular lenses, subconjunctival lenses, intracorneal lenses, and surgical shunts / implants (eg, stents or glaucoma shunts) that can be placed in the eye capsule.

In a preferred embodiment, the insert is in the form of a contact lens. The lens can be made of any suitable material known in the art. The lens material can be formed by polymerization of one or more monomers and optionally one or more prepolymers. The material may include photoinitiators, visual field stains, UV inhibitors and / or photosensitive materials.

A preferred group of lens materials are water soluble and / or dissolvable prepolymers. Preferably, the material comprises one or more prepolymers that are essentially pure (eg ultrafiltered). Preferred prepolymers include water-soluble crosslinked poly (vinyl alcohol) prepolymers (described in US Pat. Nos. 5,583,163 and 6,303,687); isocyanate-terminated polyurethanes and ethylenically unsaturated amines (primary or secondary amines) or Vinyl-terminated water-soluble polyurethane obtained by reaction with an ethylenically unsaturated monohydroxy compound (isocyanate-terminated polyurethane is at least one polyalkylene glycol, a compound containing at least two hydroxyl groups, and at least one compound containing two or more isocyanate groups) A derivative of polyvinyl alcohol, polyethyleneimine or polyvinylamine (see, for example, US Pat. No. 5,849,841); water-soluble solution described in US Pat. No. 6,479,587 Crosslinked polyurea prepolymers; crosslinked polyacrylamides; crosslinked statistical copolymers of vinyl lactam, MMA and comonomers described in European Patent EP-A-0655470 and US Pat. No. 5,712,356; European Patents EP-A-0712867 Cross-linked copolymers of vinyl lactam, vinyl acetate and vinyl alcohol as described in US Pat. No. 5,656,840; polyether-polyester copolymers having cross-linked side chains as described in European Patent EP-A-0932635; European Patent EP Branched polyalkylene glycol-urethane prepolymers described in A-0958315 and US Pat. No. 6,165,408; polyalkylene glycols described in European Patent EP-A-0961941 and US Pat. No. 6,221,303 Le - tetra (meth) acrylate prepolymer; and includes a cross-linked polyallylamine gluconolactone prepolymers described in International patent WO-A-00/31150.

The lens may include a hydrogel material. Generally, hydrogel materials are polymeric materials that can absorb at least 10% by weight of water when fully hydrated. Hydrogel materials are poly (vinyl alcohol) (PVA), modified PVA (eg Nerfilcon A ™), poly (hydroxyethyl methacrylate, poly (vinyl pyrrolidone), PVA with poly (carboxylic acid) (eg carbopol), Including poly (ethylene glycol), polyacrylamide, polymethacrylamide, silicone-containing hydrogel, polyurethane, polyurea and the like.

The device may also be an implantable ophthalmic device. The glucose level in tears may be much lower than the blood glucose level. With an implantable ophthalmic sensor, it is possible to observe glucose levels in body fluids or interstitial fluid that may be much higher than the glucose levels in tears. The device is preferably in the form of a subconjunctival implant, intracorneal lens, stent or glaucoma shunt.

The holographic support medium can have a hologram disposed therein and can exhibit one or more of the characteristics of the sensing mechanism described herein. The hologram can be placed on or in part or all of the support medium. Particularly in the case of contact lenses, the support medium may be integral with the device, for example, the lens body itself may contain or form a holographic support medium.

The support medium preferably comprises an unmodified or modified matrix having viscoelastic properties that change upon interaction with the analyte species. For example, the matrix can be formed by copolymerization of comonomers derived from (meth) acrylamide and / or (meth) acrylate. In particular, HEMA (hydroxyethyl methacrylate) monomer can be easily polymerized and crosslinked. HEMA polymers are widely used as support materials because they are swellable, hydrophilic and biocompatible.

It is preferable to embed the element in the contact lens after obtaining a contact lens type device by holographic element formation. For example, contact lens sensors can be obtained with the following protocol:
(A) forming a polymerizable holographic sensor (eg with a boronic acid phenyl ligand) on a surface such as a glass slide;
(B) cross-linking this layer after coating a layer of polyvinyl alcohol (PVA), preferably “Nelfilcon ™” on the sensor surface;
(C) Extract all toxic components from the coated sensor (eg, overnight at 40 ° C. using a 1: 1 mixture of methanol: water) and then autoclave;
(D) removing the sensor from the glass slide and cutting out a disk about 4 mm in diameter therefrom;
(E) Insert the disc into a contact lens mold containing contact lenses and PVA, preferably Nerfilcon ™, and after cross-linking the components are autoclaved to form the final lens.

The holographic sensor used in the present invention generally includes a holographic support medium, and a hologram is disposed on the entire medium. The physical properties of the medium may change due to the interaction between the support medium and the specimen. This change causes a change in the optical characteristics (polarizability, reflectivity, refractive index, absorbance, etc.) of the holographic element. If something changes during the reproduction of a hologram using non-ionizing electromagnetic radiation that is broadband incident light, for example, a change in color or intensity can be observed.

Sensors can be made by the methods disclosed in International Patents WO-A-95 / 26499, WO-A-99 / 63408 and WO-A-03 / 087879. The contents of the above specification are referred to in this specification.

More than one type of hologram can be supported on or in the holographic element. When the optical characteristics of the hologram change, the radiation emitted from the hologram changes, and this change can be detected. By arranging the holographic element to a specific size, it is possible to sense two independent events / species and emit the radiation in two different directions simultaneously or separately. The holographic elements may be arranged in an orderly manner.

Changes in the optical characteristics of the holographic element can be observed with a light source of non-ionizing radiation (for example, visible light). The degree of interaction between the holographic medium and the specimen type is reflected in the degree of change in physical properties detected as a change in optical characteristics (preferably a wavelength shift of non-ionizing radiation).

The changing properties of the holographic element may be any physical property such as charge density, volume, shape, density, viscosity, strength, hardness, charge, hydrophobicity, expansion, consistency, crosslink density and the like. When the physical properties change, the optical characteristics of the holographic element such as polarizability, reflectance, refractive index, or absorbance change.

There are many basic methods for changing optical properties by changing physical properties. The physical properties are preferably that the volume of the support medium changes and then the holographic fringes of the holographic element change. This change can be achieved by incorporating specific groups into the support matrix and changing the support medium, for example, by changing the conformation, charge, or degree of crosslinking of these groups through interaction with the analyte. It is. Examples of such groups include conjugated groups that specifically bind to the analyte species. In addition to the above, the charge content of the active water, solvent or support medium varies. In this case, the holographic support medium is preferably in the form of a gel.

Analyte molecules capable of reacting with at least two functional groups in the device may form reversible crosslinks between different portions of the support matrix to change the viscoelastic properties of the support matrix. Therefore, when the support matrix changes in an environment containing a solvent, the support matrix is reduced and the fringe spacing is narrowed. Specificity may be imparted by ensuring that specific binding sites are provided in the medium.

The support medium may include a receptor that can specifically bind to or interact with the analyte. Suitable receptors include antibodies, lectins, hormone receptors, drug receptors, enzymes, aptamers, nucleic acids, nucleic acid analogs and fragments thereof.

The receptor can be incorporated into the support medium by any suitable method known in the art. For example, the prepolymer and acceptor may contain a pair of functional groups; the two components can be covalently linked to each other. Further, it is possible to incorporate a receptor into a vinyl monomer that is a component of the lens forming material.

One parameter that determines the response of the system is the degree of crosslinking. If the number of crosslinking points due to monomer polymerization is too large, the polymer film becomes too hard and complex formation between the polymer and the analyte binding group becomes relatively small, which is not preferable. This may prevent the support medium from expanding.

As an example of a glucose sensor, a hydrogel-based hologram may have a support medium containing pendant glucose groups and a lectin, preferably concanavalin A (conA). Lectins bind to pendant glucose groups and act as crosslinks in the polymer structure. In the presence of free diffusible glucose, the degree of cross-linking will decrease as the polymer-attached glucose from the binding site on the lectin is replaced with glucose in solution, and the polymer will swell. The volume change of the hydrogel film containing pendant glucose groups and conA can be observed with a reflection hologram. A change in hydrogel volume changes the fringe spacing of the holographic structure, which can subsequently shift the peak wavelength of the spectral reflection response.

In such a holographic sensor, the aqueous system is preferable because the lectin is protected from exposure to an organic solvent in the aqueous system. Examples of suitable glucose components include high molecular weight dextran, and monomers allyl glucoside and 2-glycosyloxyethyl methacrylate (GEMA). Dextran, which is not inherently polymerizable, can be captured during the polymerization of monomers based on acrylamide; allyl glucoside and GEMA can be polymerized individually or with comonomers. It is preferred to prepare the polymer in the form of a thin film on a glass support.

The holographic glucose sensor may include any suitable glucose receptor, particularly a receptor that allows a reversible change in the physical properties of the support medium for glucose binding. For example, the support medium may contain pendant boronic acid groups such as phenylboronic acid or derivatives thereof. Two adjacent diol groups of glucose bind to the boronic acid group during the reversible condensation reaction. Accordingly, in the holographic element, a boronate ester is formed by the reaction of glucose and the pendant phenylboronic acid group, and the support medium is expanded. Theoretically, it is considered that a Donan potential is generated by a negatively charged boronic ester and water enters the support medium. This extension is observed as a shift of the maximum reflectivity to the long wavelength side. The sensing ability of boronic acid groups is strongly dependent on the external morphology of the molecule and the aromatic species in which the boronic acid group is present. Therefore, it is possible to prepare various glucose-sensitive probes having affinity such as mM for blood glucose and μM for tear glucose. Preferred boronic acid groups include those described in International Patent WO-A-04 / 081624.

Boronic acid compounds, in particular phenylboronic acid compounds, can be used for detection of various carbohydrates, and therefore have wide use as receptors. In physiological fluids, most of the sugars are found on glycoproteins and other macromolecular structures, that is, they cannot be bound to the boron group of the support medium because they are already bound. The lack of sex is not a problem. Glucose is the only sugar that is released at relatively high concentrations. However, lactic acid ester (lactic acid) is an α-hydroxy acid and binds to a boronic acid group, and since it is generally at a higher concentration in the eye fluid than glucose, it can be problematic.

By incorporating a lactic acid ester blocking group in the device, the problem of lactate ester interference can be addressed. For example, the support medium may have negatively charged groups, and the degree of charge will be apparent to those skilled in the art, since lactate esters are generally negatively charged in physiological fluids. An example of such a group is glycolic acid, which can be incorporated into the support medium by polymerization of monomers (including, for example, acrylamide glycolic acid). The negatively charged glycolic acid moiety competes with glucose and lactate for the phenylboronic acid moiety, but prevents lactate but not glucose. Further, for example, the boron acceptor itself may have a substantially negative charge or polarizability due to a coordinate bond with a boron atom having a suitable electron donating group. An example of such a boronic acid is 5-fluoro-2-methylacrylamide phenylboronic acid. Or attachment of the negatively charged group to the phenyl group of the boronic acid phenyl acceptor is also mentioned. The surface of the holographic element or device may be negatively charged to reduce the effects of interference by lactate esters.

The incorporation of pendant amine groups in the support medium can also enhance the glucose selectivity of the sensor. Formation of a highly reactive tetrahedral conformation around the boron atom can be promoted by the nitrogen atom of the amine group forming an intramolecular bond with the boron atom.

The support medium may contain one or more macrocyclic groups such as crown ethers that reversibly bind to various ionic species. Crown ethers are known to reversibly bind to Group I and Group II metal ions. Therefore, the presence of the specimen can be continuously observed by fixing the crown ether specific to the ionic specimen in the support medium.

The following examples illustrate the invention.

Contact lenses were made using the protocol described above. The embedded holographic element contains 12 mol% 3-acrylamidophenylboronic acid, the synthesis of which is described in international patent WO-A-04 / 081624.

A lens was placed in the eyes of a human volunteer and a glucose bolus 44 g was ingested. The response of the contact lens sensor was measured for reflection wavelength shift. Direct observation of blood glucose levels with a conventional glucose sensor was also performed.

FIG. 1 shows the response of a contact lens sensor, and FIG. 2 shows the response of a blood glucose sensor. It can be seen that the response of the two sensors is similar and the peak level absorption of glucose is t = about 25 minutes.

Experiments similar to Example 1 were performed using ophthalmic implants containing sensors. The support medium was coated with Nelfilcon ™ (Cibavision).

The experiment was performed by implanting the device subcutaneously under the eyes of a rabbit instead of a human volunteer. The rabbits were then anesthetized with a xylazine-based protocol to raise blood glucose levels to levels common in diabetic patients (see Cameron et al., Diabetes Technology & Therapeutics, 2001, 3, 201-207). Thereafter, the glucose concentration was observed with the implant. Blood glucose levels were again observed directly.

FIG. 3 shows the response of the holographic implant and FIG. 4 shows the response of the blood glucose sensor. Similar to Example 1, the responses of the two sensors are similar.

A holographic support medium was formed by copolymerizing 13 mol% 5-fluoro-2-methylacrylamide phenylboronic acid (synthesized by International Patent WO-A-04 / 081624) and 3% MBA in acrylamide. Thereafter, a holographic image was recorded in the obtained medium, and glucose in PBS was detected with a sensor at pH 7.4 and a temperature of 30 ° C. Similar experiments were performed to test the sensor response to lactate esters.

The results are shown in FIG. Due to oxygen and nitrogen based electron donating groups coordinated to the boron atom of the boronic acid phenyl acceptor, selectivity for glucose was improved over selectivity for lactate esters. These groups increase the negative change around the boron atom.

2% (w / v) dimethyl sulfoxide solution of 2-dimethoxy-2-phenylacetophenone (free radical initiator) by polymerization of 12 mol% 3-acrylamidophenylboronic acid, 12 mol% acrylamide glycolic acid and 76 mol% acrylamide Was used to obtain a medium. Holograms were recorded in the medium and the resulting sensors were tested for their response to glucose and lactate.

The results are shown in FIG. The negative charge at the acidic site caused the polymer medium to swell significantly, and the presence of acrylamide glycolic acid reduced the sensor response to the two analytes. However, the sensor responded better to glucose than to lactate because the glycolic acid component has a negative charge and prevents lactate without significantly affecting glucose binding.

3-acrylamide phenylboronic acid 11.9 mol%, N- [3- (dimethylamino) propyl] acrylamide 9.2 mol%, methylenebisacrylamide 2.9 mol%, and acrylamide 76 mol% in UV light A support medium was formed by copolymerization with exposure to time. The silver ions in the acetic acid solution diffused into the medium, and the acidic solution prevented the “misting phenomenon” of silver due to the amine component. Holograms were recorded in the medium and the resulting sensors were tested for their response to glucose and lactate.

The results are shown in FIG. The sensor was selective for glucose over lactate; the peak wavelength shift of lactate was only about 12% that of glucose at the same concentration. Also, the wavelength shift is negative for glucose, but the lactate ester bond shows a positive shift. The presence of “background” (4 mM) lactate was negligible for the sensor response to glucose.

The response of a contact lens sensor is shown. The response of a blood glucose sensor is shown. The response of the holographic implant is shown. The response of a blood glucose sensor is shown. The result of Example 3 is shown. The result of Example 4 is shown. The result of Example 5 is shown.

Claims (17)

An ophthalmic device,
It has a holographic element including a medium and a hologram disposed on the medium, and changes in the physical properties of the medium change the optical characteristics of the element, and changes occur due to the interaction between the medium and the specimen in the eye fluid. Features device. The apparatus of claim 1, wherein the medium is a polymer. The apparatus according to claim 2, wherein the medium is obtained by polymerization of a monomer containing acrylamide. 4. The device according to claim 1, wherein the holographic element does not contain silver. The apparatus according to claim 1, wherein the interaction is a chemical reaction. 6. A device according to claim 5, wherein the reaction is reversible. The apparatus according to claim 1, wherein the specimen is glucose. 8. A device according to claim 7, wherein the medium comprises phenylboronic acid groups. 9. The apparatus according to claim 8, wherein the medium is obtained by polymerization of a monomer containing 3-acrylamidophenylboronic acid or 5-fluoro-2-methacrylamidephenylboronic acid. 10. Device according to claim 8 or 9, characterized in that the medium comprises a group capable of preventing lactate esters, which group comprises a substantially negative change. The device according to claim 10, wherein boron in the boronic acid group has a substantially negative change. The apparatus according to claim 10 or 11, wherein the medium is formed by polymerization of a monomer containing acrylamide glycolic acid. 13. A device according to any one of claims 7 to 12, characterized in that the medium comprises an amine group. The device according to claim 1, wherein the device is a contact lens. 14. Device according to any one of the preceding claims, characterized in that it is implantable. A method for detecting a specimen in ocular fluid,
16. A method comprising the detection of any change in the optical properties of a holographic element of a device according to any one of claims 1 to 15 present with a liquid in the eye. 15. The method of manufacturing a device according to claim 14, comprising contact between the holographic element and the contact lens, wherein the contact area between the element and the lens is crosslinkable and includes bridging of the contact area.

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